Genetic Variant ARHGDIB:p.Asp118Gly (chr12-14944829-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001175.7(ARHGDIB):c.353A>G(p.Asp118Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ARHGDIB
NM_001175.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35

Variant links:

Genes affected

ARHGDIB (HGNC:679): (Rho GDP dissociation inhibitor beta) Members of the Rho (or ARH) protein family (see MIM 165390) and other Ras-related small GTP-binding proteins (see MIM 179520) are involved in diverse cellular events, including cell signaling, proliferation, cytoskeletal organization, and secretion. The GTP-binding proteins are active only in the GTP-bound state. At least 3 classes of proteins tightly regulate cycling between the GTP-bound and GDP-bound states: GTPase-activating proteins (GAPs), guanine nucleotide-releasing factors (GRFs), and GDP-dissociation inhibitors (GDIs). The GDIs, including ARHGDIB, decrease the rate of GDP dissociation from Ras-like GTPases (summary by Scherle et al., 1993 [PubMed 8356058]).[supplied by OMIM, Dec 2010]

ARHGDIB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIB	NM_001175.7 link	c.353A>G	p.Asp118Gly	missense_variant	Exon 5 of 6	ENST00000228945.9	NP_001166.3	P52566A0A024RAS5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGDIB	ENST00000228945.9 link	c.353A>G	p.Asp118Gly	missense_variant	Exon 5 of 6	1	NM_001175.7	ENSP00000228945.4		P52566

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250346

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461042

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.353A>G (p.D118G) alteration is located in exon 5 (coding exon 4) of the ARHGDIB gene. This alteration results from a A to G substitution at nucleotide position 353, causing the aspartic acid (D) at amino acid position 118 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

0.0077

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;D;.

Eigen

Benign

0.064

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

.;.;D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

L;L;L;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;.

Polyphen

0.0020

B;B;B;.

Vest4

0.51

MutPred

0.58

Gain of catalytic residue at S121 (P = 2e-04);Gain of catalytic residue at S121 (P = 2e-04);Gain of catalytic residue at S121 (P = 2e-04);Gain of catalytic residue at S121 (P = 2e-04);

MVP

0.63

MPC

0.51

ClinPred

0.79

GERP RS

4.3

Varity_R

0.80

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over